scholarly journals C9orf72 Intermediate Repeats Confer Genetic Risk for Severe COVID-19 Pneumonia Independently of Age

2021 ◽  
Vol 22 (13) ◽  
pp. 6991
Author(s):  
Isabella Zanella ◽  
Eliana Zacchi ◽  
Simone Piva ◽  
Massimiliano Filosto ◽  
Giada Beligni ◽  
...  
Keyword(s):  
Myeloid Cells ◽  
Immune Functions ◽  
Non Invasive ◽  
Host Determinants ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
C9orf72 Gene ◽  
Pathogenic Process ◽  
Lateral Sclerosis ◽  
Independent Cohort

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lysosome functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

scholarly journals Modelling C9orf72-Related Amyotrophic Lateral Sclerosis in Zebrafish

Biomedicines ◽  
2020 ◽  
Vol 8 (10) ◽  
pp. 440
Author(s):  
Gabrielle Fortier ◽  
Zoé Butti ◽  
Shunmoogum A. Patten
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Neurological Diseases ◽  
Disease Model ◽  
Model Organism ◽  
Model Systems ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
C9orf72 Gene ◽  
Pharmacological Manipulations ◽  
Lateral Sclerosis

A hexanucleotide repeat expansion within the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and its discovery has revolutionized our understanding of this devastating disease. Model systems are a valuable tool for studying ALS pathobiology and potential therapies. The zebrafish (Danio rerio) has particularly become a useful model organism to study neurological diseases, including ALS, due to high genetic and physiological homology to mammals, and sensitivity to various genetic and pharmacological manipulations. In this review we summarize the zebrafish models that have been used to study the pathology of C9orf72-related ALS. We discuss their value in providing mechanistic insights and their potential use for drug discovery.

scholarly journals Disease Mechanisms and Therapeutic Approaches in C9orf72 ALS-FTD

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 601
Author(s):  
Keith Mayl ◽  
Christopher E. Shaw ◽  
Youn-Bok Lee
Keyword(s):  
The Body ◽  
The Novel ◽  
Therapeutic Approaches ◽  
Gain Of Function ◽  
Pathogenic Mechanisms ◽  
Hexanucleotide Repeat ◽  
Primary Driver ◽  
Hexanucleotide Repeat Expansion ◽  
Expansion Mutation ◽  
Lateral Sclerosis

A hexanucleotide repeat expansion mutation in the first intron of C9orf72 is the most common known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Since the discovery in 2011, numerous pathogenic mechanisms, including both loss and gain of function, have been proposed. The body of work overall suggests that toxic gain of function arising from bidirectionally transcribed repeat RNA is likely to be the primary driver of disease. In this review, we outline the key pathogenic mechanisms that have been proposed to date and discuss some of the novel therapeutic approaches currently in development.

scholarly journals C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex

2013 ◽  
Vol 70 (6) ◽  
pp. 742 ◽  
Author(s):  
Beth A. Dombroski ◽  
Douglas R. Galasko ◽  
Ignacio F. Mata ◽  
Cyrus P. Zabetian ◽  
Ulla-Katrina Craig ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Repeat Expansion ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Lateral Sclerosis

scholarly journals Who and Why? Requests for Presymptomatic Genetic Testing for Amyotrophic Lateral Sclerosis/Frontotemporal Dementia vs Huntington Disease

2020 ◽  
Vol 7 (1) ◽  
pp. e538
Author(s):  
Maria del Mar Amador ◽  
Marcela Gargiulo ◽  
Christilla Boucher ◽  
Ariane Herson ◽  
Stéphanie Staraci ◽  
...  
Keyword(s):  
At Risk ◽  
Amyotrophic Lateral Sclerosis ◽  
Frontotemporal Dementia ◽  
Huntington Disease ◽  
Dropout Rate ◽  
Time Frame ◽  
Hexanucleotide Repeat ◽  
Hexanucleotide Repeat Expansion ◽  
Added Uncertainty ◽  
Lateral Sclerosis

ObjectiveWe aimed to describe the population of subjects seeking presymptomatic counseling for amyotrophic lateral sclerosis and/or frontotemporal dementia (ALS/FTD) and compared them with those demanding the well-established presymptomatic test for Huntington disease (HD).MethodsWe retrospectively examined the requests of a cohort of individuals at risk of familial ALS/FTD and 1 at risk of HD over the same time frame of 11 years. The individuals were seen in the referral center of our neurogenetics unit.ResultsOf the 106 presymptomatic testing (PT) requests from subjects at risk of ALS/FTD, 65% were seen in the last 3 years. Over two-thirds of the subjects were at risk of carrying mutations responsible for ALS, FTD, or both. Sixty-two percent of the subjects came from families with a known hexanucleotide repeat expansion in C9ORF72. During the same period, we counseled 840 subjects at risk of HD. Subjects at risk of ALS/FTD had the presymptomatic test significantly sooner after being aware of their risk, but were older than those at risk of HD. The youngest subjects requesting the test had the highest disease load in the family (p < 0.05).ConclusionsDemands for PT for ALS/FTD have been increasingly growing, particularly since the discovery of the C9ORF72 gene. The major specificity of the genetic counseling for these diseases is the unpredictability of the clinical phenotype for most of the genes involved. Awareness of this added uncertainty does not prevent individuals from taking the test, as the dropout rate is not higher than that for HD.

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